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Nutritional Deficiency Anemias
Darshan Mehta, MD Department of Internal Medicine University of Illinois-Chicago
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Anemia Definition Parameters of Anemia
Reduction in blood transport of oxygen due to a deficiency in red blood cells Parameters of Anemia Hematocrit – Percentage of blood volume as RBCs Hemoglobin – Concentration of hemoglobin in blood Mean Corpuscular Volume (MCV) – Average size of RBC Mean Corpuscular Hemoglobin (MCH) – Average hemoglobin content of RBC RDW – range of deviation around average
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Mechanisms of Anemia Marrow production defects (hypoproliferation)
Low reticulocyte count Little or no change in red cell morphology (a normocytic, normochromic anemia Red cell maturation defects (ineffective erythropoiesis) Slight to moderately elevated reticulocyte count Macrocytic or microcytic anemia Decreased red cell survival (blood loss/ hemolysis).
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Classification of anemias by MCV
Microcytic (<80 fL) Iron deficiency Thalassemia Anemia of chronic disease Macrocytic (>100 fL) Vitamin B12 deficiency Folate deficiency Myelodysplasia Chemotherapy Liver disease Increased reticulocytosis Myxedema Normocytic Anemia of chronic disease Aplasia Protein-energy malnutrition Chronic renal failure Post-hemorrhagic
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Initial Evaluation History and Physical Exam Laboratory evaluation
Eating ice or clay Dyspnea Conjunctival pallor Chest Pain Medications Laboratory evaluation CBC with differential Peripheral Smear Reticulocyte count Iron Studies
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Nutrient Roles in Erythropoesis
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Iron Stores Humans contain ~2.5 g of iron, with g circulating as part of heme in hemoglobin Another ~0.3 g found in myoglobin, in heme in cytochromes, and in Fe-S complexes Iron stored in body primarily as protein complexes (ferritin and hemosiderin)
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Nutritional Iron Balance
Intake Dietary iron intake Medicinal iron Red cell transfusions Injection of iron complexes Excretion Gastrointestinal bleeding Menses Losses can be as much as mg/menstrual cycle Other forms of bleeding Loss of epidermal cells from the skin and gut
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Iron Absorption Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories) Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed Heme iron> Organic iron (Ferrous gluconate) > Inorganic iron (ferrous sulfate) Average iron intake in an adult male is 15 mg/d with 6% absorption; average female, the daily intake is 11 mg/d with 12% absorption Acid pH and presence of reducing agents: ascorbic acid (vitamin C) reduces Fe+++ to Fe++ which promotes passage across intestinal mucosa Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50% Takes place in the mucosa of the proximal small intestine Absorption increase to 20% in iron-deficient persons
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Dietary Sources of Iron
Red meat > poultry & fish In U.S., 20 mg iron added/lb of flour Baked bread contains ~28 mg iron/kg Equivalent to the iron content of beef Iron cooking pots Plants are generally not good sources because of oxalate, phytate, tannins, etc. Spinach has a lot of iron, but has ~780 mg oxalate/100 g Note - Heme iron absorption from diet not affected by ascorbate or phytate
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Iron Exchange 80% of iron passing through the plasma transferrin pool is recycled from broken-down red cells Absorption of about 1 mg/d is required from the diet in men, 1.4 mg/d in women to maintain homeostasis
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Iron Deficiency Anemia
Facts and Figures Most common cause of anemia 500 million cases worldwide Prevalence is higher in less developed countries Unique Physical Exam findings Cheilosis fissures at the corners of the mouth Koilonychia spooning of the fingernails
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Causes of Iron Deficiency
Increased demand for iron and/or hematopoiesis Rapid growth in infancy or adolescence Pregnancy Erythropoietin therapy Increased iron loss Chronic blood loss Menses Acute blood loss Blood donation Phlebotomy as treatment for polycythemia vera Decreased iron intake or absorption Inadequate diet Malabsorption from disease (sprue, Crohn's disease) Malabsorption from surgery (post-gastrectomy) Acute or chronic inflammation
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Iron Deficiency Anemia
Hypochromic red cell Microcytic cell Target cell
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Stages of Iron Deficiency
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Treatment of Iron Deficiency
Red Blood Cell Transfusion Oral Iron Therapy Ferrous sulfate Ferrous fumarate Ferrous gluconate Parenteral Iron
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Iron Supplementation in special populations
Pregnant Women During the last two trimesters, daily iron requirements increase to 5 to 6 mg Infancy Normal-term infants are born with sufficient iron stores to prevent iron deficiency for the first 4–5 months of life Thereafter, enough iron needs to be absorbed to keep pace with the needs of rapid growth Nutritional iron deficiency is most common between 6 and 24 months of life
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Megaloblastic Anemia Due to impaired DNA synthesis
Affects cells primarily having relatively rapid turnover, especially hematopoietic precursors and gastrointestinal epithelial cells Cell division is sluggish, but cytoplasmic development progresses normally, so megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. Megaloblastic erythroid progenitors tend to be destroyed in the marrow Marrow cellularity is often increased but production of red blood cells (RBC) is decreased
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Causes of Megaloblastic Anemia
Vitamin B12 Deficiency Inadequate intake: vegans (rare) Malabsorption Defective release of cobalamin from food Gastric achlorhydria Partial gastrectomy Drugs that block acid secretion Inadequate production of intrinsic factor (IF) Pernicious anemia Total gastrectomy Disorders of terminal ileum Sprue Regional enteritis Intestinal resection Competition for cobalamin Fish tapeworm (Diphyllobothrium latum) Bacteria: "blind loop" syndrome Drugs: p-aminosalicylic acid, colchicine, neomycin
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Clinical Manifestations of Vitamin B12 Deficiency
Hematologic Macrocytic Anemia Gastrointestinal Glossitis Anorexia Diarrhea Neurologic (found in 3/4th of individuals with pernicious anemia) Numbness and paresthesia in the extremities, Weakness, Ataxia Sphincter disturbances Disturbances of mentation Mild irritability and forgetfulness to severe dementia or frank psychosis. Demyelination, Axonal degeneration, and then Neuronal death Last stage is irreversible
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Megaloblastic Anemia Macrocytic RBC Hypersegmented Neutrophil
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Vitamin B12 Absorption – Oral Phase
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Vitamin B12 Absorption – Gastric Phase
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Vitamin B12 Absorption – Intestinal Phase
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Vitamin B12 Deficiency Any interruption along this path can result in cobalamin deficiency Gastrectomy results in low production of IF Terminal ileal resection (>100 cm), decreases the site of absorption of B12-IF complex
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Pernicious Anemia Most common cause of cobalamin deficiency
Caused by the absence of IF Atrophy of the mucosa Autoimmune destruction of parietal cells Seen in individuals of northern European descent and African Americans Men and women are equally affected Disease of the elderly, the average patient presenting near age 60
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Diagnosis of Vitamin B12 Deficiency
Macrocytosis Peripheral blood smear Cobalamin levels Elevated serum methylmalonic acid and homocysteine levels Schilling Test
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Schilling Test Measures B12 deficiency Detects IF deficiency
Detects abnormal results in patients with genetic defects in B12 absorption, bacterial overgrowth of the small bowel, resection/bypass of terminal ileum, and pancreatic insufficiency
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Stage 1 Oral dose of radiolabeled cobalamin given simultaneously with an IM injection unlabeled cobalamin 24 Hour Urine collection Amount radiolabeled activity is measured Normal absorption of B12 and normal renal function will excrete > 7% of radiolabeled B12
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Stage 2 If stage 1 is abnormal, then test is repeated following 60 mg of oral IF If the level of urinary radiolabeled B12 normalizes, then this indicates pernicious anemia
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Stage 3 Small intestine bacterial overgrowth may cause B12 malabsorption and an abnormal result in stage 1 that is not corrected with IF administration in stage 2 Broad spectrum antibiotics are given for one week to eliminate intestinal bacteria and then stage 1 should normalize
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Stage 4 If pancreatic insufficiency exists, B12 malabsorption may occur Normalization after pancreatic enzyme therapy suggests pancreatic origin
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Causes of Megaloblastic Anemia
Folate Deficiency Inadequate intake: unbalanced diet (common in alcoholics, teenagers, some infants) Increased requirements Pregnancy Infancy Malignancy Increased hematopoiesis (chronic hemolytic anemias) Chronic exfoliative skin disorders Hemodialysis Malabsorption Sprue Drugs: Phenytoin, barbiturates, (?) ethanol Impaired metabolism Inhibitors of dihydrofolate reductase: methotrexate, pyrimethamine, triamterene, pentamidine, trimethoprim Alcohol Rare enzyme deficiencies: dihydrofolate reductase, others
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Treatment of Vitamin B12 Deficiency
Replacement therapy Parenteral treatment given weekly intramuscularly for 8 weeks, followed by intramuscularly every month for the rest of the patient's life. Daily oral replacement therapy
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Folate Deficiency More often malnourished than those with cobalamin deficiency Gastrointestinal manifestations More widespread and more severe than those of pernicious anemia Diarrhea is often present Cheilosis Glossitis Neurologic abnormalities do not occur
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Stages of folate deficiency
Negative folate balance (decreased serum folate) Decreased RBC folate levels and hypersegmented neutrophils Macroovalocytes, increased MCV, and decreased hemoglobin
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Diagnosis of folate deficiency
Peripheral blood and bone marrow biopsy look exactly like B12 deficiency Plasma folate <3 ng/ml—fluctuates with recent dietary intake RBC folate—more reliable of tissue stores <140 ng/ml Only increased serum homocysteine levels but NOT serum methylmalonic acid levels
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Treatment of folate deficiency
Oral replacement therapy Folate prophylaxis Women planning pregnancy are advised to take 400 g folic acid daily before conception and until 12 weeks of pregnancy to prevent neural-tube defects (5 mg/day for women with a previous affected pregnancy) Folate fortification of cereal grains at 1·4 mg/kg has been made mandatory in the USA as an additional method of improving the folate status of the population. Prophylactic folate is also recommended in other states of increased demand such as long-term hemodialysis and chronic haemolytic disorders
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Inappropriate Treatment of Pernicious Anemia With Folate
Vitamin B12 deficiency anemia can be temporarily corrected by folate supplementation However, this does not correct the neurologic deficits Folate “draws” vitamin B12 away from neurologic system for RBC production and can exacerbate combined systems degeneration
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